Collaborative Research: Data-driven integration of biological with in-silico experiments to determine mechanistic effects of N-glycosylation on cellular electromechanical functions

本研究的完成将使用混合实验、统计和计算方法的重复过程描述n -糖基化及其对肌肉细胞功能的调节的基本作用。糖基化是将糖残基以共价键加到蛋白质上的过程，是参与细胞通讯的蛋白质的一种常见修饰。生理线索调节糖基化过程，蛋白质糖基化影响心肌细胞的电和收缩功能，从而表明糖基化在肌肉细胞生理中的基础和动态作用。通过这项研究获得的新知识将被整合到实验和计算肌肉细胞生物学交叉的跨学科教育计划中，旨在吸引和留住学生科学家，重点关注来自代表性不足群体的学生/学员。为此，将开发以下内容：1)关于实验和计算肌肉细胞生物学的大规模开放在线课程；2)基于web的用户友好型心肌细胞模型和分析算法；3)心肌细胞模型原型VR系统的初步工作，使研究人员和学生能够积极实践，感受并实时与细胞机电功能互动；4)为高中生提供心血管生理学的交互式实验室体验。最近的数据表明糖基化调节、电信号和肌细胞收缩之间存在联系。虽然由于缺乏适当的模型，这种假定联系的机制仍然难以捉摸，但在这里，将使用一个迭代过程来确定负责的细胞机制，该过程将已建立的生物物理和生化技术与新开发的糖合成方法相结合，严格的计算机建模，并在新创建的更合适的动物模型上进行统计实验设计，以描述血糖变化对心肌细胞生理学的功能影响。描述这种机制的影响和意义被物种之间的糖基化机制高度可变的事实所扩大。因此，存在于生物体之间的不同糖基化可能导致蛋白质功能的调节，然后可预测地改变细胞活动。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Completion of this research will describe the fundamental roles for N-glycosylation and its regulation on muscle cell function using a repetitive process blending experimental, statistical, and computational methods. Glycosylation - the process of covalent addition of sugar residues to proteins - is a common modification to proteins involved in cellular communication. Physiological cues regulate the glycosylation process and protein glycosylation impacts electrical and contractile functions of cardiac muscle cells, thereby suggesting a fundamental and dynamic role for glycosylation in muscle cell physiology. The new knowledge gained through this research will be integrated into an interdisciplinary education program at the intersection of experimental and computational muscle cell biology that is aimed at engaging and retaining student scientists, focusing on students/trainees from underrepresented groups. To do so, the following will be developed: 1) A massive open online course on experimental and computational muscle cell biology, 2) Web-based user-friendly myocyte models and analytical algorithms, 3) Initial work on a prototype VR system of myocyte models that enable researchers and students to actively practice, feel, and interact with cellular electromechanical function in real time, and 4) An interactive laboratory experience in cardiovascular physiology for high school students. Recent data suggest a link among regulated glycosylation, electrical signaling, and myocyte contraction. While mechanisms for this putative link remain elusive due to a lack of appropriate models, here, the responsible cellular mechanisms will be determined using an iterative process that combines established biophysical and biochemical techniques with newly developed glycomic methods, rigorous in-silico modeling, and statistical experimental design on a newly created and more appropriate animal model to describe the functional impact of a changing glycome on cardiomyocyte physiology. The impact and significance of describing such a mechanism are broadened by the fact that the glycosylation machinery among species is highly variable. Thus, the differential glycosylation that exists among organisms likely results in modulated protein function that then predictably alters cellular activities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.